A drastic reduction in the life span of cystatin C L68Q carriers due to life-style changes during the last two centuries

Astridur Palsdottir, Agnar Helgason, Snaebjorn Palsson, Hans Tomas Bjornsson, Birkir Thor Bragason, Solveig Gretarsdottir, Unnur Thorsteinsdottir, Elias Olafsson, Kari Stefansson

Research output: Contribution to journalArticle

Abstract

Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here, we report, based both on linkage disequilibrium and genealogical evidence, that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period. A mutation with such radically different phenotypic effects in reaction to normal variation in human life-style not only opens the possibility of preventive strategies for HCCAA, but it may also provide novel insights into the complex relationship between genotype and environment in human disease.

Original languageEnglish (US)
Article numbere1000099
JournalPLoS Genetics
Volume4
Issue number6
DOIs
StatePublished - Jun 2008

Fingerprint

cystatins
Cystatin C
lifestyle
Life Style
mutation
Mutation
amyloid
inheritance (genetics)
extended families
Genealogy and Heraldry
Iceland
penetrance
genealogy
Penetrance
Intracranial Hemorrhages
Linkage Disequilibrium
common ancestry
linkage disequilibrium
young adults
human diseases

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

A drastic reduction in the life span of cystatin C L68Q carriers due to life-style changes during the last two centuries. / Palsdottir, Astridur; Helgason, Agnar; Palsson, Snaebjorn; Bjornsson, Hans Tomas; Bragason, Birkir Thor; Gretarsdottir, Solveig; Thorsteinsdottir, Unnur; Olafsson, Elias; Stefansson, Kari.

In: PLoS Genetics, Vol. 4, No. 6, e1000099, 06.2008.

Research output: Contribution to journalArticle

Palsdottir, A, Helgason, A, Palsson, S, Bjornsson, HT, Bragason, BT, Gretarsdottir, S, Thorsteinsdottir, U, Olafsson, E & Stefansson, K 2008, 'A drastic reduction in the life span of cystatin C L68Q carriers due to life-style changes during the last two centuries', PLoS Genetics, vol. 4, no. 6, e1000099. https://doi.org/10.1371/journal.pgen.1000099
Palsdottir, Astridur ; Helgason, Agnar ; Palsson, Snaebjorn ; Bjornsson, Hans Tomas ; Bragason, Birkir Thor ; Gretarsdottir, Solveig ; Thorsteinsdottir, Unnur ; Olafsson, Elias ; Stefansson, Kari. / A drastic reduction in the life span of cystatin C L68Q carriers due to life-style changes during the last two centuries. In: PLoS Genetics. 2008 ; Vol. 4, No. 6.
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